Heteroaromatic bicyclic derivatives useful as anticancer agents

ABSTRACT

The invention relates to compounds of the formula 1  
                 
 
     and to pharmaceutically acceptable salts and solvates thereof, wherein A, X, R 1 , R 3  and R 4  are as defined herein. The invention also relates to methods of treating abnormal cell growth in mammals by administering the compounds of formula 1 and to pharmaceutical compositions for treating such disorders which contain the compounds of formula 1. The invention also relates to methods of preparing the compounds of formula 1.

BACKGROUND OF THE INVENTION

[0001] This invention relates to novel bicyclic derivatives that areuseful in the treatment of abnormal cell growth, such as cancer, inmammals. This invention also relates to a method of using such compoundsin the treatment of abnormal cell growth in mammals, especially humans,and to pharmaceutical compositions containing such compounds.

[0002] It is known that a cell may become cancerous by virtue of thetransformation of a portion of its DNA into an oncogene (i.e., a genewhich, on activation, leads to the formation of malignant tumor cells).Many oncogenes encode proteins that are aberrant tyrosine kinasescapable of causing cell transformation. Alternatively, theoverexpression of a normal proto-oncogenic tyrosine kinase may alsoresult in proliferative disorders, sometimes resulting in a malignantphenotype.

[0003] Receptor tyrosine kinases are enzymes which span the cellmembrane and possess an extracellular binding domain for growth factorssuch as epidermal growth factor, a transmembrane domain, and anintracellular portion which functions as a kinase to phosphorylatespecific tyrosine residues in proteins and hence to influence cellproliferation. Other receptor tyrosine kinases include c-erbB-2, c-met,tie-2, PDGFr, FGFr, VEGF and TGF-β. It is known that such kinases arefrequently aberrantly expressed in common human cancers such as breastcancer, gastrointestinal cancer such as colon, rectal or stomach cancer,leukemia, and ovarian, bronchial or pancreatic cancer. It has also beenshown that epidermal growth factor receptor (EGFR), which possessestyrosine kinase activity, is mutated and/or overexpressed in many humancancers such as brain, lung, squamous cell, bladder, gastric, breast,head and neck, oesophageal, gynecological and thyroid tumors.

[0004] Accordingly, it has been recognized that inhibitors of receptortyrosine kinases are useful as selective inhibitors of the growth ofmammalian cancer cells. For example, erbstatin, a tyrosine kinaseinhibitor, selectively attenuates the growth in athymic nude mice of atransplanted human mammary carcinoma which expresses epidermal growthfactor receptor tyrosine kinase (EGFR) but is without effect on thegrowth of another carcinoma which does not express the EGF receptor.Thus, the compounds of the present invention, which are selectiveinhibitors of certain receptor tyrosine kinases, are useful in thetreatment of abnormal cell growth, in particular cancer, in mammals.

[0005] Various other compounds, such as styrene derivatives, have alsobeen shown to possess tyrosine kinase inhibitory properties. Morerecently, five European patent publications, namely EP 0 566 226 A1(published Oct. 20, 1993), EP 0 602 851 A1 (published Jun. 22, 1994), EP0 635 507 A1 (published Jan. 25, 1995), EP 0 635 498 A1 (published Jan.25, 1995), and EP 0 520 722 A1 (published Dec. 30, 1992), refer tocertain bicyclic derivatives, in particular quinazoline derivatives, aspossessing anti-cancer properties that result from their tyrosine kinaseinhibitory properties. Also, World Patent Application WO 92/20642(published Nov. 26, 1992), refers to certain bis-mono and bicyclic aryland heteroaryl compounds as tyrosine kinase inhibitors that are usefulin inhibiting abnormal cell proliferation. World Patent ApplicationsWO96/16960 (published Jun. 6, 1996), WO 96/09294 (published Mar. 6,1996), WO 97/30034 (published Aug. 21, 1997), WO 98/02434 (publishedJan. 22, 1998), WO 98/02437 (published Jan. 22, 1998), and WO 98/02438(published Jan. 22, 1998), also refer to substituted bicyclicheteroaromatic derivatives as tyrosine kinase inhibitors that are usefulfor the same purpose.

SUMMARY OF THE INVENTION

[0006] The present invention relates to compounds of the formula 1

[0007] and to pharmaceutically acceptable salts and solvates thereof,wherein:

[0008] X is N or CH;

[0009] A represents a fused 5, 6 or 7-membered ring optionallycontaining 1 to 4 heteroatoms which may be the same or different andwhich are selected from —N(R¹)—, O, and S(O)_(j), wherein j is aninteger from 0 to 2, the fused ring containing a total of 1, 2 or 3double bonds inclusive of the bond in the pyridine or pyrimidine ring towhich it is fused wherein the R¹ group attached to the nitrogen isabsent if a double bond includes the foregoing optional nitrogen moiety—N(R¹)—, with the proviso that the fused ring does not form part of apurine and that the fused ring does not contain two adjacent O orS(O)_(j) atoms, and wherein the carbon atoms of the A moiety areoptionally substituted with 1 to 3 R⁵ groups;

[0010] each R¹ and R² is independently H or C₁-C₆ alkyl;

[0011] R³ is —(CR¹R²)_(m)—R⁸ wherein m is 0 or 1;

[0012] or R¹ and R³ are taken together to form a group of the formula

[0013] wherein said group is optionally substituted with 1 to 3 R⁵groups;

[0014] R⁴ is —(CR¹R²)_(t)(C₆-C₁₀ aryl) or —(CR¹R²)_(t)(4-10 memberedheterocyclic), wherein t is an integer from 0 to 5, wherein said R⁴groups are substituted with 1 to 3 groups independently selected from—(CR¹R²)_(q)NR¹R⁹, —(CR¹R²)_(q)NR⁹(C₁-C₆alkanoyl),—(CR¹R²)_(q)O(CR¹R²)_(r)R⁹, and —(CR¹R²)_(q)R⁹ wherein q and r are eachindependently an integer from 0 to 5, and wherein the heterocyclic, aryland alkyl moieties of the foregoing groups are optionally substitutedwith 1 to 3 R¹⁰ groups;

[0015] each R⁵ is independently selected from halo, hydroxy, —NR¹R²,C₁-C₆ alkyl, trifluoromethyl, C₁-C₆ alkoxy, and trifluoromethoxy;

[0016] each R⁶ and R⁷ is independently selected from H, C₁-C₆ alkyl,—(CR¹R²)_(t)(C₆-C₁₀ aryl), and —(CR¹R²)_(t)(4-10 membered heterocyclic),wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of theheterocyclic group are optionally substituted with an oxo (═O) moiety,and the alkyl, aryl and heterocyclic moieties of the foregoing R⁶ and R⁷groups are optionally substituted with 1 to 3 substituents independentlyselected from halo, cyano, nitro, —NR¹R², trifluoromethyl,trifluoromethoxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxy,and C₁-C₆ alkoxy;

[0017] each R⁸ is independently selected from —CR¹R²)_(t)(C₆-C₁₀ aryl)and —(CR¹R²)_(t)(4-10 membered heterocyclic), wherein t is an integerfrom 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group areoptionally substituted with an oxo (═O) moiety, and each of theforegoing R⁸ groups is optionally substituted with 1 to 5 R¹⁰ groups;

[0018] R⁹ is a fused or bridged bicyclic ring or a spirocyclic ring,wherein said ring contains from 5 to 12 carbon atoms in which up to 2carbon atoms are optionally replaced with a hetero moiety selected fromO, S(O)_(j) wherein j is an integer from 0 to 2, and —NR¹¹—, providedthat two O atoms, two S(O), moieties, an O atom and a S(O)_(j) moiety,an N atom and an S atom, or an N atom and an O atom are not attacheddirectly to each other, and wherein said ring is saturated or partiallyunsaturated with up to two carbon-carbon double bonds, and the carbonatoms of said ring are optionally substituted with 1 to 4 R¹⁰ groups;

[0019] or where R⁹ is as —NR¹R⁹ then R⁹ optionally can be taken togetherwith R¹ and the nitrogen to which R¹ and R⁹ are attached to form a fusedor bridged bicyclic ring or a spirocyclic ring, wherein said ring issaturated and contains from 5 to 12 carbon atoms in which up to 2 carbonatoms are optionally replaced with a hetero moiety selected from O,S(O), wherein j is an integer from 0 to 2, and —NR¹—, provided that twoO atoms, two S(O)_(j) moieties, or an O atom and a S(O)_(j) moiety arenot attached directly to each other, and wherein the carbon atoms ofsaid rings are optionally substituted with 1 to 4 R¹⁰ groups;

[0020] each R¹⁰ is independently selected from halo, cyano, nitro,trifluoromethoxy, trifluoromethyl, azido, hydroxy, C₁-C₆ alkoxy, C₁-C₁₀alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C(O)R⁵, —C(O)OR⁶, —OC(O)R⁶,—NR⁶C(O)R⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷, —SO₂NR⁶R⁷, —S(O)_(j)(C₁-C₆alkyl) wherein j is an integer from 0 to 2, —(CR¹R²)_(t)(C⁶-C¹⁰ aryl),—(CR¹R²)_(t)(4-10 membered heterocyclic),—(CR¹R²)_(q)C(O)(CR¹R²)_(t)(C⁶-C¹⁰ aryl),—(CR¹R²)^(q)C(O)(CR¹R²)^(t)(4-10 membered heterocyclic),—(CR¹R²)_(t)O(CR¹R²)_(q)(C₆-C₁₀ aryl), —(CR¹R²)_(t)O(CR¹R²)_(q)(4-10membered heterocyclic), —(CR¹R²)_(q)SO₂(CR¹R²)_(t)(C₆-C₁₀ aryl), and—(CR¹R²)_(q)SO₂(CR¹R²)_(t)(4-10 membered heterocyclic), wherein q and tare each independently an integer from 0 to 5, 1 or 2 ring carbon atomsof the heterocyclic moieties of the foregoing R¹⁰ groups are optionallysubstituted with an oxo (═O) moiety, and the alkyl, alkenyl, alkynyl,aryl and heterocyclic moieties of the foregoing R¹⁰ groups areoptionally substituted with 1 to 3 substituents independently selectedfrom halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR⁶,—C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷,C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, —(CR¹R²)_(t)(C₆-C₁₀ aryl), and—(CR¹R²)_(t)(4-10 membered heterocyclic), wherein t is an integer from 0to 5;

[0021] R¹¹ is H, C₁-C₆ alkyl, —C(O)R⁶ or —SO₂R⁶;

[0022] and wherein any of the above-mentioned substituents comprising aCH₃ (methyl), CH₂ (methylene), or CH (methine) group which is notattached to a halogeno, SO or SO₂ group or to a N, O or S atomoptionally bears on said group a substituent selected from hydroxy,halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and —NR¹R².

[0023] In a specific embodiment of the present invention, the A moietyof the compounds of formula 1 is selected from

[0024] wherein the above A moieties bear an R⁴ group as a substituentand optionally bear 1 to 3 R⁵ groups as substituents.

[0025] Other specific embodiments of the compounds of formula 1 includethose wherein A is selected from

[0026] wherein the above A moieties bear an R⁴ group as a substituentand optionally bear 1 to 3 R⁵ groups as substituents.

[0027] Other specific embodiments of the compounds of formula 1 includethose wherein A is selected from

[0028] wherein the above A moieties bear an R⁴ group as a substituentand optionally bear 1 to 3 R⁵ groups as substituents.

[0029] Other specific embodiments of the compounds of formula 1 includethose wherein A is selected from

[0030] wherein the above A moieties bear an R⁴ group as a substituentand optionally bear 1 to 3 R⁵ groups as substituents.

[0031] Other specific embodiments of the compounds of formula 1 includethose wherein A is

[0032] wherein the above A moieties bear an R⁴ group as a substituentand optionally bear 1 to 3 R⁵ groups as substituents.

[0033] Other specific embodiments of the compounds of formula 1 includethose wherein R⁴ is —(CR¹R²)_(t)(C₆-C₁₀ aryl) or —(CR¹R²)_(t)(4-10membered heterocyclic), wherein t is an integer from 0 to 5, whereinsaid R⁴ groups are substituted with 1 to 3 groups independently selectedfrom —(CR¹R²)_(q)NR¹R⁹, —(CR¹R²)_(q)NR⁹(C₁-C₆ alkanoyl),—(CR¹R²)_(q)O(CR¹R²)_(r)R⁹, and —(CR¹R²)_(q)R⁹ wherein q and r are eachindependently an integer from 0 to 3, and wherein the heterocyclic, aryland alkyl moieties of the foregoing groups are optionally substitutedwith 1 to 3 R¹⁰ groups.

[0034] Other specific embodiments of the compounds of formula 1 includethose wherein R³ is —(CR¹R²)_(m)—R⁸ wherein m is 0 or 1 and R⁸ isselected from —(CR¹R²)_(t)(phenyl), —(CR¹R²)_(t)(pyridyl),—(CR¹R²)_(t)(pyrimidinyl), —(CR¹R²)_(t)(indolyl), —CR¹R²)_(t)(indazolyl)and —(CR¹R²)_(t)(benzimidazolyl), wherein t is an integer from 0 to 5,and each of the foregoing R⁸ groups is optionally substituted with 1 to5 R¹⁰ groups.

[0035] Other specific embodiments of the compounds of formula 1 includethose selected from the group consisting of:

[0036]{6-[4-(6-Amino-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-(4-phenoxy-phenyl)-amine;

[0037] (3-554-[4-(4-Benzyl-phenylamino)-quinazolin-6-yl]-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0038](3-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0039](3-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl-)-methanol;

[0040](6-{4-[(1-Aza-bicyclo[2.2.2]oct-3-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-4-phenyl)-amine;

[0041](6-{4-[(1-Aza-bicyclo[2.2.2]oct-3-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(4-benzyl-phenyl)-amine;

[0042]6-{4-[(1-Aza-bicyclo[2.2.2]oct-3-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(1-benzenesulfonyl-1H-indol-5-yl)-amine;

[0043]6-{4-[(3-Aza-bicyclo[3.1.0]hex-6-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(4-phenoxy-phenyl)-amine;

[0044]3-{4-[4-(4-Benzyl-phenylamino)-quinazolin-6-yl]-benzylamino}-8-methyl-8-aza-bicyclo[3.2.1]octan-6-ol;

[0045](4-Benzyl-phenyl)-{6-[4-(6-methoxymethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-amine

[0046]{6-[4-(6-Methoxymethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-(4-phenoxy-phenyl)-amine;

[0047](3-{4-[4-(4-[1,2,3]Thiadiazol-5-yl-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0048](3-{4-[4-(4-Cyclohexyl-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0049](3-{4-[4-(4-p-Tolyloxy-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0050](3-{4-[4-(Biphenyl-4-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0051](3-{4-[4-(4-Ethyl-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0052]4-{6-[4-(6-Hydroxymethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-ylamino}-N-phenyl-benzamide;

[0053][3-(4-{4-[1-(Propane-2-sulfonyl)-1H-indol-5-ylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]methanol;

[0054](3-{4-[4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0055](1-Benzenesulfonyl-1H-indol-5-yl)-(6-{4-[(3-oxa-bicyclo[3.1.0]hex-6-ylamino)-methyl-]-phenyl}-quinazolin-4-yl)-amine;

[0056]8-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-8-aza-bicyclo[3.1.0]octan-3-ol;

[0057]8-(4-{4-[1-Propane-2-sulfonyl)-1H-indol-5-ylamino]-quinazolin-6-yl}-benzyl)-8-aza-bicyclo[3.2.1]octan-3-ol;

[0058]8-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol;

[0059]8-{4-[4-(1-Benzyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-8-aza-bicyclo[3.2.1]-octan-3-ol;

[0060](3-{4-[4-(6-Phenoxy-pyridin-3-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0061](3-{5-[4-(4-Benzyl-phenylamino)-quinazolin-6-yl]-pyridin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0062]{3-[4-(4-Phenoxy-phenylamino)-quinazolin-6ylmethyl]-3-aza-bicyclo[3.1.0]hex-6-yl}methanol;

[0063](5-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-5-aza-spiro[2.5]oct-1-yl)methanol;

[0064](5-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-5-aza-spiro[2.5]oct-1-yl)-methanol;

[0065](6-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-6-aza-spiro[2.5]oct-1-yl)-methanol;

[0066](6-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-6-azaspiro[2.5]oct-1-yl)-methanol;

[0067](5-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]benzyl}-5-aza-spiro[2.4]hept-1-yl)-methanol;

[0068](5-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-5-aza-spiro[2.4]hept-1-yl)-methanol;

[0069](5-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-5-aza-spiro[2.5]oct-1-yl)-methanol;

[0070] and the pharmaceutically acceptable salts and solvates of theforegoing compounds.

[0071] This invention also relates to a method for the treatment ofabnormal cell growth in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the formula 1,as defined above, or a pharmaceutically acceptable salt or solvatethereof, that is effective in treating abnormal cell growth. In oneembodiment of this method, the abnormal cell growth is cancer,including, but not limited to, lung cancer, bone cancer, pancreaticcancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer of the anal region, stomach cancer, colon cancer, breast cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, carcinoma of the cervix, carcinoma of the vagina, carcinomaof the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of thesmall intestine, cancer of the endocrine system, cancer of the thyroidgland, cancer of the parathyroid gland, cancer of the adrenal gland,sarcoma of soft tissue, cancer of the urethra, cancer of the penis,prostate cancer, chronic or acute leukemia, lymphocytic lymphomas,cancer of the bladder, cancer of the kidney or ureter, renal cellcarcinoma, carcinoma of the renal pelvis, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, or a combination of one or more of theforegoing cancers. In another embodiment of said method, said abnormalcell growth is a benign proliferative disease, including, but notlimited to, psoriasis, benign prostatic hypertrophy or restinosis.

[0072] This invention also relates to a method for the treatment ofabnormal cell growth in a mammal which comprises administering to saidmammal an amount of a compound of formula 1, or a pharmaceuticallyacceptable salt or solvate thereof, that is effective in treatingabnormal cell growth in combination with an anti-tumor agent selectedfrom the group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, antibodies, cytotoxics, anti-hormones, andanti-androgens.

[0073] This invention also relates to a pharmaceutical composition forthe treatment of abnormal cell growth in a mammal, including a human,comprising an amount of a compound of the formula 1, as defined above,or a pharmaceutically acceptable salt or solvate thereof, that iseffective in treating abnormal cell growth, and a pharmaceuticallyacceptable carrier. In one embodiment of said composition, said abnormalcell growth is cancer, including, but not limited to, lung cancer, bonecancer, pancreatic cancer, skin cancer, cancer of the head or neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer, cancer of the anal region, stomach cancer, colon cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In anotherembodiment of said pharmaceutical composition, said abnormal cell growthis a benign proliferative disease, including, but not limited to,psoriasis, benign prostatic hypertrophy or restinosis.

[0074] The invention also relates to a pharmaceutical composition forthe treatment of abnormal cell growth in a mammal, including a human,which comprises an amount of a compound of formula 1, as defined above,or a pharmaceutically acceptable salt or solvate thereof, that iseffective in treating abnormal cell growth in combination with apharmaceutically acceptable carrier and an anti-tumor agent selectedfrom the group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, anti-hormones, and anti-androgens.

[0075] The invention also relates to a method of preparing a compound ofthe formula 1

[0076] and to pharmaceutically acceptable salts and solvates thereof,wherein A, X, R¹, R⁴ and R³ are as defined above, which comprises either(a) reacting a compound of the formula 5 with a compound of the formula6

[0077] wherein Z is a leaving group and A, X, R¹, R³, and R⁴ are asdefined above, or (b) reacting a compound of the formula 2 with acompound of the formula 6

[0078] wherein X, A, R¹, and R³ are as defined above and Z¹ is anactivating group to provide an intermediate of the formula 7

[0079] wherein Z¹, X, A, R¹, and R³ are as defined above, and treatingthe compound of formula 7 with a coupling partner of the formulaX¹—(CR¹R²)_(t)(C₆-C₁₀ aryl) or X¹—(CR¹R²)_(t)(4-10 memberedheterocyclic), wherein t, R¹ and R² are as defined above as provided inthe definition of R⁴, the aryl and heterocyclic groups of the foregoinggroups are substituted with a group that includes an aldehyde or acidmoiety, and X¹ is —B(OH)₂ or —Sn(C₁-C₅ alkyl)₃, to provide a compound offormula 8

[0080] wherein X, A, R¹, and R³ are as defined above, and Z² is—(CR¹R²)_(t)(C₆-C₁₀ aryl) or —(CR¹R²)_(t)(4-10 membered heterocyclic),wherein t, R¹ and R² are as defined above as provided in the definitionof R⁴, and the aryl and heterocyclic groups of the foregoing Z² groupsare substituted with a group that includes an aldehyde or acid moiety,and modifying said acid or aldehyde moiety to introduce a group selectedfrom —(CR¹R²)_(q)NR¹R⁹, —(CR¹R²)_(q)NR⁹(C₁-C₆ alkanoyl),—(CR¹R²)_(q)OR⁹, and —(CR¹R²)_(q)R⁹, wherein R¹, R², R⁹ and q are asdefined above.

[0081] “Abnormal cell growth”, as used herein, unless otherwiseindicated, refers to cell growth that is independent of normalregulatory mechanisms (e.g., loss of contact inhibition). This includesthe abnormal growth of: (1) tumor cells (tumors) that proliferate byexpressing a mutated tyrosine kinase or overexpression of a receptortyrosine kinase; (2) benign and malignant cells of other proliferativediseases in which aberrant tyrosine kinase activation occurs; and (4)any tumors that proliferate by receptor tyrosine kinases.

[0082] The term “treating”, as used herein, unless otherwise indicated,means reversing, alleviating, inhibiting the progress of, or preventingthe disorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

[0083] The term “halo”, as used herein, unless otherwise indicated,means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro,chloro and bromo.

[0084] The term “alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight,branched, or cyclic moieties (including fused and bridged bicyclic andspirocyclic moieties), or a combination of the foregoing moieties. Foran alkyl group to have cyclic moieties, the group must have at leastthree carbon atoms.

[0085] The term “alkenyl”, as used herein, unless otherwise indicated,includes alkyl moieties having at least one carbon-carbon double bondwherein alkyl is as defined above and including E and Z isomers of saidalkenyl moiety.

[0086] The term “alkynyl”, as used herein, unless otherwise indicated,includes alkyl moieties having at least one carbon-carbon triple bondwherein alkyl is as defined above.

[0087] The term “alkoxy”, as used herein, unless otherwise indicated,includes O-alkyl groups wherein alkyl is as defined above.

[0088] The term “aryl”, as used herein, unless otherwise indicated,includes an organic radical derived from an aromatic hydrocarbon byremoval of one hydrogen, such as phenyl or naphthyl.

[0089] The term “4-10 membered heterocyclic”, as used herein, unlessotherwise indicated, includes aromatic and non-aromatic heterocyclicgroups containing one to four heteroatoms each selected from O, S and N,wherein each heterocyclic group has from 4-10 atoms in its ring system,and with the proviso that the ring of said group does not contain twoadjacent O or S atoms. Non-aromatic heterocyclic groups include groupshaving only 4 atoms in their ring system, but aromatic heterocyclicgroups must have at least 5 atoms in their ring system. The heterocyclicgroups include benzo-fused ring systems. An example of a 4 memberedheterocyclic group is azetidinyl (derived from azetidine). An example ofa 5 membered heterocyclic group is thiazolyl and an example of a 10membered heterocyclic group is quinolinyl. Examples of non-aromaticheterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups, as derived from the groups listedabove, may be C-attached or N-attached where such is possible. Forinstance, a group derived from pyrrole may be pyrrol-1-yl (N-attached)or pyrrol-3-yl (C-attached). Further, a group derived from imidazole maybe imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). An exampleof a heterocyclic group wherein 2 ring carbon atoms are substituted withoxo (═O) moieties is 1,1-dioxo-thiomorpholinyl.

[0090] The phrase “pharmaceutically acceptable salt(s)”, as used herein,unless otherwise indicated, includes salts of acidic or basic groupswhich may be present in the compounds of formula 1. The compounds offormula 1 that are basic in nature are capable of forming a wide varietyof salts with various inorganic and organic acids. The acids that may beused to prepare pharmaceutically acceptable acid addition salts of suchbasic compounds of formula 1 are those that form non-toxic acid additionsalts, i.e., salts containing pharmacologically acceptable anions, suchas the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate,estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate,laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate,napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate,pantothenate, phospate/diphosphate, polygalacturonate, salicylate,stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate,triethiodode, and valerate salts.

[0091] In the compounds of formula 1, where terms such as (CR¹R²)_(q) or(CR¹R²)_(t) are used, R¹ and R² may vary with each iteration of q or tabove 1. For instance, where q or t is 2 the terms (CR¹R²)_(q) or(CR¹R²)_(t) may equal —CH₂CH₂—, or —CH(CH₃)C(CH₂CH₃)(CH₂CH₂CH₃)—, or anynumber of similar moieties falling within the scope of the definitionsof R¹ and R². Further, as noted above, any substituents comprising a CH₃(methyl), CH₂ (methylene), or CH (methine) group which is not attachedto a halogeno, SO or SO₂ group or to a N, O or S atom optionally bearson said group a substituent selected from hydroxy, C₁-C₄ alkoxy and—NR¹R².

[0092] Certain compounds of formula 1 may have asymmetric centers andtherefore exist in different enantiomeric forms. All optical isomers andstereoisomers of the compounds of formula 1, and mixtures thereof, areconsidered to be within the scope of the invention. With respect to thecompounds of formula 1, the invention includes the use of a racemate,one or more enantiomeric forms, one or more diastereomeric forms, ormixtures thereof. The compounds of formula 1 may also exist astautomers. This invention relates to the use of all such tautomers andmixtures thereof.

[0093] The subject invention also includes isotopically-labelledcompounds, which are identical to those recited in Formula 1, but forthe fact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of Formula 1 of this invention andprodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

DETAILED DESCRIPTION OF THE INVENTION

[0094] General synthetic methods which may be referred to for preparingthe compounds of the present invention are provided in U.S. Pat. No.5,747,498 (issued May 5, 1998), U.S. patent application Ser. No.08/953078 (filed Oct. 17, 1997), WO 98/02434 (published Jan. 22, 1998),WO 98/02438 (published Jan. 22, 1998), WO 96/40142 (published Dec. 19,1996), WO 96/09294 (published Mar. 6, 1996), WO 97/03069 (published Jan.30, 1997), WO 95/19774 (published Jul. 27, 1995) and WO 97/13771(published Apr. 17, 1997). The foregoing patents and patent applicationsare incorporated herein by reference in their entirety. Certain startingmaterials may be prepared according to methods familiar to those skilledin the art and certain synthetic modifications may be done according tomethods familiar to those skilled in the art. A standard procedure forpreparing 6-iodoquinazolinone is provided in Stevenson, T. M.,Kazmierczak, F., Leonard, N. J., J. Org. Chem. 1986, 51, 5, p. 616.Palladium-catalyzed boronic acid couplings are described in Miyaura, N.,Yanagi, T., Suzuki, A. Syn. Comm. 1981, 11, 7, p. 513. Reduction ofaromatic nitro groups can be performed by methods outlined in Brown, R.K., Nelson, N. A. J. Org. Chem. 1954, p. 5149; Yuste, R., Saldana, M,Walls, F., Tet. Lett. 1982, 23, 2, p. 147; or in WO/9609294, referred toabove. Nitro substituted N1-phenylsulfonylindoles/indazoles can beprepared by the methods found in Sundberg, R. J., Bloom, J. D., J. Org.Chem. 1980, 45, 17, p. 3382; Ottoni, O. et al. Tetrahedron, 1998, 54,13915; or Boger, Dale L. et. al.; J. Org. Chem; 55; 4; 1990; 1379..Substituted nitro N1-benzylindoles/indazoles can be prepared by methodsfound in Makosza, M.; Owczarczyk, Z.; J.Org.Chem., 54, 21, 1989, 5094;Adebayo, Adelaide T. O. M., Bowman, W. Russell, Salt, W. G., J. Chem.Soc. Perkin Trans.1, 1989, 1415; or WO 98/02434, referred to above.Benzyloxy-nitrobenzene intermediates may be prepared by methods found inWO 98/02434, referred to above.

[0095] Alternatively, arylmethoxy, or aryloxy nitrobenzene derivativesmay be prepared from halo nitrobenzene precursors by nucleophilicdisplacement of the halide with an appropriate alcohol as described inDinsmore, C. J. et. al., Bioorg. Med. Chem. Lett., 7, 10, 1997, 1345; orLoupy, A. et. al., Synth. Commun., 20, 18, 1990, 2855; or Brunelle, D.J. Tet. Lett., 25, 32, 1984, 3383. Fused and bridged bicyclic amineswere synthesized according to the methods described in: Brighty, K. E.and Castaldi, M. J., Synlett, 1996, 1097; and Momose, T. et al., J.Chem. Soc. Perkin Trans.1, 1997, 1307. Spirocyclic amines weresynthesized according to methods found in WO 92/22550. Startingmaterials, the synthesis of which is not specifically described hereinor the published references referred to above, are either commerciallyavailable or can be prepared using methods well known to those of skillin the art.

[0096] In each of the reactions discussed or illustrated in the Schemesabove, pressure is not critical unless otherwise indicated. Pressuresfrom about 0.5 atmospheres to about 5 atmospheres are generallyacceptable, and ambient pressure, i.e., about 1 atmosphere, is preferredas a matter of convenience.

[0097] Where the compound of formula 6, HNR¹R³, is an optionallysubstituted indole or indoline moiety, such compounds may be preparedaccording to one or more methods known to those skilled in the art. Suchmethods are described in PCT international patent applicationpublication number WO 95/23141 and in W. C. Sumpter and F. M. Miller,“Heterocyclic Compounds with Indole and Carbazole Systems,” in volume 8of “The Chemistry of Heterocyclic Compounds”, Interscience PublishersInc., New York (1954). Optional substituents may be included asappropriate before or after the coupling step illustrated in Scheme 1.Prior to the coupling step, primary and secondary amino moieties (otherthan said amine of formula 6, HNR¹R³) are preferably protected using anitrogen protecting group known to those skilled in the art. Suchprotecting groups and their use are described in T. W. Greene and P. G.M. Wuts, “Protective Groups in Organic Synthesis,” Second Edition, JohnWiley & Sons, New York, 1991.

[0098] With reference to Scheme 1 above, the compound of formula 1 maybe prepared by coupling the compound of formula 5, wherein X, A, and R⁴are as defined above and Z is a leaving group, such as a phenoxy or aphenoxy derivative substituted with halo, cyano, nitro, or lower alkyl,with an amine of the formula 6, HNR¹R³, wherein R¹ and R³ are as definedabove, in an anhydrous solvent, in particular a solvent selected fromDMF (N,N-dimethylformamide), DME (ethylene glycol dimethyl ether), DCE(dichloroethane), t-butanol, and phenol, or a mixture of the foregoingsolvents, a temperature within the range of about 50-150° C. for aperiod ranging from 1 to 48 hours. The compound of formula 6, HNR¹R³,may be prepared by methods known to those skilled in the art, such asreduction of nitrites, reduction of imines or enamines, reduction ofoximes, primary and secondary amides, reduction of a nitro group orreductive amination of either R¹NH₂ and R³CH(O) or R³NH₂ and R¹CH(O).The compound of formula 5 may be prepared by treating a compound offormula 4, wherein Z² is —(CR¹R²)_(t)(C₆-C₁₀ aryl) or —(CR¹R²)_(t)(4-10membered heterocyclic), wherein t, R¹ and R² are as defined above asprovided in the definition of R⁴, and the aryl and heterocyclic groupsof the foregoing groups are substituted by a group that includes analdehyde or acid moiety that may be modified to introduce one or moregroups selected from —(CR¹R²)_(q)NR¹R⁹, —(CR¹R²)_(q)NR⁹(C₁-C₆ alkanoyl,—(CR¹R²)_(q)OR⁹, and —(CR¹R²)_(q)R⁹ as provided in the definition of R⁴above. Such modifications may be done according to methods familiar tothose skilled in the art. For instance, an amine moiety may beintroduced by reductive amination of an aldehyde group. A compound ofthe formula 4 can be obtained by treating a compound of the formula 3,wherein Z¹ is an activating group, such as bromo, iodo, —N₂, or —OTF(which is —OSO₂CF₃), with a coupling partner of the formulaX¹—(CR¹R²)_(t)(C₆-C₁₀ aryl) or X¹—(CR¹R²)_(t)(4-10 memberedheterocyclic), wherein t, R¹ and R² are as defined above as provided inthe definition of R⁴, the aryl and heterocyclic groups of the foregoinggroups are substituted with a group that includes an aldehyde or acidmoiety, and X¹ is —B(OH)₂ or —Sn(C₁-C₅ alkyl)₃. This reaction isgenerally done using palladium (0) or palladium (II) catalysts in asolvent such as DMF, THF (tetrahydrofuran), toluene, dioxanes, or amixture of the foregoing solvents, at 60-100° C. for about 8-24 hours.The compound of formula 2 may be converted to the compound of formula 3wherein Z is a substituted phenoxy derivative by treating the startingcompound with an appropriate metal phenoxide, such as sodium phenolate,in a solvent, such as DMF or phenol, at a temperature ranging from about0° C. to 100° C. for a period ranging from about 2 to 24 hours.

[0099] In the alternative, compounds of the formula 1 may be preparedaccording to the synthesis outlined in Scheme 2. In Scheme 2, a compoundof the formula 1 may be obtained by treating a compound of formula 8,wherein Z² is as defined above, as described above regarding theconversion of the compound of formula 4 to a compound of formula 5. Acompound of the formula 8 may be obtained by treating a compound offormula 7, wherein Z¹ is an activating group as defined above, asdescribed above regarding the conversion of the compound of formula 3 toa compound of formula 4. A compound of formula 7 may be obtained from acompound of formula 2 by reaction with an amine of the formula 6,HNR¹R³, wherein R¹ and R³ are as defined above, in a anhydrous solvent,in particular a solvent selected from DMF, DME, DCE, t-butanol, andphenol, or a mixture of the foregoing solvents, a temperature within therange of about 50-150° C. for a period ranging from about 1 to 48 hours.

[0100] The starting compound of formula 2 may be prepared as illustratedin Scheme 3. In Scheme 3, the compound of formula 11 wherein X is NH maybe prepared from a compound of formula 9, wherein A and Z¹ are asdefined above and Z³ is OH, according to one or more proceduresdescribed in WO 95/19774, referred to above, and a compound of formula11 wherein X is CH may be prepared from a compound of formula 10,wherein A and Z¹ are as defined above, according to procedures describedin WO 95/19774, referred to above. The compound of formula 11 may beconverted to the compound of formula 2 by treating the starting compoundwith a chlorinating reagent, such as POCl₃ or ClC(O)C(O)Cl/DMF in ahalogenated solvent at a temperature ranging from about 60° C. to 150°C. for a period ranging from about 2 to 24 hours.

[0101] The compounds of the present invention may have asymmetric carbonatoms. Diasteromeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known to those skilled in the art, for example, bychromatography or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixtures into a diastereomricmixture by reaction with an appropriate optically active compound (e.g.,alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers. All such isomers, including diastereomeric mixtures andpure enantiomers are considered as part of the invention,

[0102] The compounds of formulas 1 that are basic in nature are capableof forming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate the compound of formula 1 from the reaction mixture asa pharmaceutically unacceptable salt and then simply convert the latterback to the free base compound by treatment with an alkaline reagent andsubsequently convert the latter free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent, such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is readily obtained. The desired acidsalt can also be precipitated from a solution of the free base in anorganic solvent by adding to the solution an appropriate mineral ororganic acid.

[0103] Those compounds of formula 1 that are acidic in nature arecapable of forming base salts with various pharmacologically acceptablecations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the acidic compounds of formula 1. Suchnon-toxic base salts include those derived from such pharmacologicallyacceptable cations as sodium, potassium calcium and magnesium, etc.These salts can easily be prepared by treating the corresponding acidiccompounds with an aqueous solution containing the desiredpharmacologically acceptable cations, and then evaporating the resultingsolution to dryness, preferably under reduced pressure. Alternatively,they may also be prepared by mixing lower alkanolic solutions of theacidic compounds and the desired alkali metal alkoxide together, andthen evaporating the resulting solution to dryness in the same manner asbefore. In either case, stoichiometric quantities of reagents arepreferably employed in order to ensure completeness of reaction andmaximum yields of the desired final product.

[0104] The compounds of the present invention are potent inhibitors ofthe erbB family of oncogenic and protooncogenic protein tyrosine kinasessuch as epidermal growth factor receptor (EGFR), erbB2, HER3, or HER4and thus are all adapted to therapeutic use as antiproliferative agents(e.g., anticancer) in mammals, particularly in humans. In particular,the compounds of the present invention are useful in the prevention andtreatment of a variety of human hyperproliferative disorders such asmalignant and benign tumors of the liver, kidney, bladder, breast,gastric, ovarian, colorectal, prostate, pancreatic, lung, vulval,thyroid, hepatic carcinomas, sarcomas, glioblastomas, head and neck, andother hyperplastic conditions such as benign hyperplasia of the skin(e.g., psoriasis) and benign hyperplasia of the prostate (e.g., BPH). Itis, in addition, expected that a compound of the present invention maypossess activity against a range of leukemias and lymphoid malignancies.

[0105] The compounds of the present invention may also be useful in thetreatment of additional disorders in which aberrant expressionligand/receptor interactions or activation or signalling events relatedto various protein tyrosine kinases, are involved. Such disorders mayinclude those of neuronal, glial, astrocytal, hypothalamic, and otherglandular, macrophagal, epithelial, stromal, and blastocoelic nature inwhich aberrant function, expression, activation or signalling of theerbB tyrosine kinases are involved. In addition, the compounds of thepresent invention may have therapeutic utility in inflammatory,angiogenic and immunologic disorders involving both identified and asyet unidentified tyrosine kinases that are inhibited by the compounds ofthe present invention.

[0106] The in vitro activity of the compounds of formula 1 may bedetermined by the following procedure.

[0107] The c-erbB2 kinase assay is similar to that described previouslyin Schrang et. al. Anal. Biochem. 211, 1993, p233-239. Nunc MaxiSorp96-well plates are coated by incubation overnight at 37° C. with 100 mLper well of 0.25 mg/mL Poly (Glu, Tyr) 4:1 (PGT) (Sigma Chemical Co.,St. Louis, Mo.) in PBS (phosphate buffered saline). Excess PGT isremoved by aspiration, and the plate is washed three times with washbuffer (0.1% Tween 20 in PBS). The kinase reaction is performed in 50 mLof 50 mM HEPES (pH 7.5) containing 125 mM sodium chloride, 10 mMmagnesium chloride, 0.1 mM sodium orthovanadate, 1 mM ATP, 0.48 mg/mL(24 ng/well) c-erbB2 intracellular domain. The intracellular domain ofthe erbB2 tyrosine kinase (amino acids 674-1255) is expressed as a GSTfusion protein in Baculovirus and purified by binding to and elutionfrom glutathione coated beads. The compound in DMSO (dimethylsulfoxide)is added to give a final DMSO concentration of about 2.5%.Phosphorylation was initiated by addition of ATP (adenosinetriphosphate) and proceeded for 6 minutes at room temperature, withconstant shaking. The kinase reaction is terminated by aspiration of thereaction mixture and subsequent washing with wash buffer (see above).Phosphorylated PGT is measured by 25 minutes of incubation with 50 mLper well HRP-conjugated PY54 (Oncogene Science Inc. Uniondale, N.Y.)antiphosphotyrosine antibody, diluted to 0.2 mg/mL in blocking buffer(3% BSA and 0.05% Tween 20 in PBS). Antibody is removed by aspiration,and the plate is washed 4 times with wash buffer. The colorimetricsignal is developed by addition of TMB Microwell Peroxidase Substrate(Kirkegaard and Perry, Gaithersburg, Md.), 50 mL per well, and stoppedby the addition of 0.09 M sulfuric acid, 50 mL per well. Phosphotyrosineis estimated by measurement of absorbance at 450 nm. The signal forcontrols is typically 0.6-1.2 absorbance units, with essentially nobackground in wells without the PGT substrate and is proportional to thetime of incubation for 10 minutes. Inhibitors were identified byreduction of signal relative to wells without inhibitor and IC₅₀ valuescorresponding to the concentration of compound required for 50%inhibition are determined.

[0108] The activity of the compounds of formula 1, in vivo, can bedetermine by the amount of inhibition of tumor growth by a test compoundrelative to a control. The tumor growth inhibitory effects of variouscompounds are measured according to the method of Corbett T. H., et al.,“Tumor Induction Relationships in Development of Transplantable Cancersof the Colon in Mice for Chemotherapy Assays, with a Note on CarcinogenStructure”, Cancer Res., 35, 2434-2439 (1975) and Corbett T. H., et al.,“A Mouse Colon-tumor Model for Experimental Therapy”, Cancer Chemother.Rep. (Part 2)”, 5, 169-186 (1975), with slight modifications. Tumors areinduced in the left flank by subcutaneous (sc) injection of 1-5 millionlog phase cultured tumor cells (murine FRE-ErbB2 cells or human SK-OV3ovarian carcinoma cells) suspended in 0.1 ml RPMI 1640 medium. Aftersufficient time has elapsed for the tumors to become palpable (100-150mm3 in size/5-6 mm in diameter) the test animals (athymic female mice)are treated with test compound (formulated at a concentration of 10 to15 mg/ml in 5 Gelucire) by the intraperitoneal (ip) or oral (po) routeof administration once or twice daily for 7 to 10 consecutive days. Inorder to determine an anti-tumor effect, the tumor is measured inmillimeters with a Vernier caliper across two diameters and the tumorsize (mm3) is calculated using the formula: Tumor size(mm3)=(length×[width]2)/2, according to the methods of Geran, R. I., etal. “Protocols for Screening Chemical Agents and Natural ProductsAgainst Animal Tumors and Other Biological Systems”, Third Edition,Cancer Chemother. Rep., 3, 1-104 (1972). Results are expressed aspercent inhibition, according to the formula: Inhibition(%)=(TuW_(control)−TuW_(test))/TuW_(control)×100%. The flank site oftumor implantation provides reproducible dose/response effects for avariety of chemotherapeutic agents, and the method of measurement (tumordiameter) is a reliable method for assessing tumor growth rates.

[0109] Administration of the compounds of the present invention(hereinafter the “active compound(s)”) can be effected by any methodthat enables delivery of the compounds to the site of action. Thesemethods include oral routes, intraduodenal routes, parenteral injection(including intravenous, subcutaneous, intramuscular, intravascular orinfusion), topical, and rectal administration.

[0110] The amount of the active compound administered will be dependenton the subject being treated, the severity of the disorder or condition,the rate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage isin the range of about 0.001 to about 100 mg per kg body weight per day,preferably about 1 to about 35 mg/kg/day, in single or divided doses.For a 70 kg human, this would amount to about 0.05 to about 7 g/day,preferably about 0.2 to about 2.5 g/day. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day.

[0111] The active compound may be applied as a sole therapy or mayinvolve one or more other anti-tumour substances, for example thoseselected from, for example, mitotic inhibitors, for example vinblastine;alkylating agents, for example cis-platin, carboplatin andcyclophosphamide; anti-metabolites, for example 5-fluorouracil, cytosinearabinoside and hydroxyurea, or, for example, one of the preferredanti-metabolites disclosed in European Patent Application No. 239362such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for exampleinterferon; and anti-hormones, for example anti-estrogens such asNolvadex™ (tamoxifen) or, for example anti-androgens such as Casodex™(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment.

[0112] The pharmaceutical composition may, for example, be in a formsuitable for oral administration as a tablet, capsule, pill, powder,sustained release formulations, solution, suspension, for parenteralinjection as a sterile solution, suspension or emulsion, for topicaladministration as an ointment or cream or for rectal administration as asuppository. The pharmaceutical composition may be in unit dosage formssuitable for single administration of precise dosages. Thepharmaceutical composition will include a conventional pharmaceuticalcarrier or excipient and a compound according to the invention as anactive ingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, adjuvants, etc.

[0113] Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

[0114] Suitable pharmaceutical carriers include inert diluents orfillers, water and various organic solvents. The pharmaceuticalcompositions may, if desired, contain additional ingredients such asflavorings, binders, excipients and the like. Thus for oraladministration, tablets containing various excipients, such as citricacid may be employed together with various disintegrants such as starch,alginic acid and certain complex silicates and with binding agents suchas sucrose, gelatin and acacia. Additionally, lubricating agents such asmagnesium stearate, sodium lauryl sulfate and talc are often useful fortableting purposes. Solid compositions of a similar type may also beemployed in soft and hard filled gelatin capsules. Preferred materials,therefor, include lactose or milk sugar and high molecular weightpolyethylene glycols. When aqueous suspensions or elixirs are desiredfor oral administration the active compound therein may be combined withvarious sweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

[0115] Methods of preparing various pharmaceutical compositions with aspecific amount of active compound are known, or will be apparent, tothose skilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

[0116] The examples and preparations provided below further illustrateand exemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples, “Ac”means acetyl, “Er” means ethyl, “Me” means methyl, and “Bu” means butyl.

[0117] Where HPLC chromatography is referred to in the preparations andexamples below, the general conditions used, unless otherwise indicated,are as follows. The column used is a ZORBAX™ RXC18 column (manufacturedby Hewlett Packard) of 150 mm distance and 4.6 mm interior diameter. Thesamples are run on a Hewlett Packard-1100 systemA gradient solventmethod is used running 100 percent ammonium acetate/acetic acid buffer(0.2 M) to 100 percent acetonitrile over 10 minutes. The system thenproceeds on a wash cycle with 100 percent acetonitrile for 1.5 minutesand then 100 percent buffer solution for 3 minutes. The flow rate overthis period is a constant 3 ml/minute.

[0118] Method A: Synthesis of(3-{4-[4-(1-Cyclopropylmethyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol(18)

[0119] 6-Iodo-4-guinazolinone (12):

[0120] A solution of 2-amino-5-iodobenzoic acid (26.3 g, 100 mmol) andformamidine acetate (13.5 g, 130 mmol) in ethanol (400 mL) was refluxedfor 20 hours. After cooling to 0° C., the solid product was collected byfiltration. Further drying in vacuo provided 6-iodo-4-quinazolinone 12(22.0 g, 81%) as a grey crystalline solid. 1H NMR (400 MHz; DMSO-d₆) δ:12.38 (br. s, 1H), 8.35 (d, 1H), 8.05-8.10 (m, 2H), 7.43 (dd, 1H). LRMS:272.9 (MH+).

[0121] 6-iodo-4-chloroquinazoline (13):

[0122] To a stirred solution of DMF (N,N-dimethylformamide) (6.3 mL) inDCE (dichloroethane) (20 mL) cooled to 0° C. was added dropwise asolution of oxalyl chloride (60 mL of a 2M solution in DCE). Afteraddition was complete, the cooling bath was removed and6-iodo-3H-quinazolinone 12 (10 g, 36.8 mmol) was added as a solid. Theresulting mixture was heated to reflux under nitrogen for 3 hours. Uponcooling to room temperature, the reaction was quenched cautiously withH₂O. CH₂Cl₂ was added and the bilayer transferred to a separatoryfunnel. The aqueous layer was extracted with CH₂Cl₂ (2×50 mL) and thecombined organic layers dried (Na₂SO₄). The solvent was removed in vacuoto provide a yellow solid which was triturated with diethyl ether toremove any remaining impurities. The resulting yellow solid obtained byfiltration was shown to be pure by NMR. For compound 13: ¹HNMR (CDCl₃,400 MHz): δ: 9.05 (s, 1H), 8.65 (d, 1H), 8.21 (dd, 1H), 7.78 (d, 1H).

[0123] 6-iodo-4-phenoxyguinazoline (14):

[0124] A suspension of NaH (washed free of mineral oil) in DMF (40 mL)was cooled to 0° C. and a solution of phenol (5.65 g, 60 mmol) in DMF(20 mL) was added dropwise. Upon completion of addition,6-iodo-4-chloroquinazoline 13 (14.6 g, 50.3 mmol) was added as a solidin small portions. The cooling bath was moved and the reaction mixturewas stirred at room temperature for 2 hours. The mixture was thenquenched with water (200 mL), diluted with EtOAc (300 mL) andtransferred to a separatory funnel. The organic layer was washed withdilute aqueous NaOH, water and brine and dried over Na₂SO₄. Filtrationof the solids and removal of the solvent provided6-iodo-4-phenoxyquinazoline 14 (17.2 g, 98%) as a yellow solid. ¹H NMR(400 MHz; CDCl₃): δ: 8.74 (d, 1H), 8.14 (s, 1H), 8.12 (dd, 1H), 7.71 (d,1H), 7.49 (dd, 2H), 7.32 (t, 1H), 7.22 (m, 2H).

[0125] 4-(4-Phenoxy-quinazolin-6-yl)benzaldehyde (15):

[0126] To a solution of toluene (211 mL) in a 1.0 L round-bottom flaskequipped with a reflux condenser was added1,4-bis(diphenyl)phosphino)-butane (1.22 g, 2.87 mmol) andbis(benzonitrile)dichloro-palladium (1.1 g, 2.87 mmol). The resultingsolution was stirred at room temperature for 30 minutes followed by theaddition of THF (tetrahydrofuran) (255 mL) and EtOH (115 mL). To theresulting mixture was added 6-iodo-4-phenoxy-quinazoline 14 (5.0 g, 14.4mmol), 4-formylphenylboronic acid (4.3 g, 28.7 mmol) and aqueous 1MNa₂CO₃ (29 mL). The mixture was heated at reflux under an atmosphere ofN₂ for 18 hours. The reaction mixture was filtered hot and the solventremoved under reduced pressure. The residue was taken up in CHCl₃ andwashed with water, brine, and dried (MgSO₄). The solvent was removedunder reduced pressure and the residue was purified using flashchromatography (silica gel, EtOAc/hexanes 4:6) to provide (4.42 g, 13.54mmol) 4-(4-phenoxy-quinazolin-6-yl)benzaldehyde 15 in 94% yield. ¹H NMR(CDCl₃) δ 7.26 (m, 3H), 2.88 (m, 1H), 7.51 (M, 2H), 7.92 (d, 2H, J=8.4Hz), 8.02 (d, 2H, J=8 Hz), 8.11 (d, 1H, J=8.8 Hz), 8.20 (dd, 1H, J=2.4and 8.8 Hz), 8.63 (d, 1H, J=2.4 Hz), 8.79 (s, 1H); MS (Cl) m/e 326(M⁺+1, 100).

[0127]3-[4-(4-Phenoxy-quinazolin-6-yl)-benzyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-methanol(16):

[0128] To a solution of 1:1 CHCl₃ and MeOH in a round-bottom flask underN₂ was added (3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 17 (2.27 g, 19.7mmol) which was allowed to stir at room temperature for fifteen minutes.To the amine solution was added 4-(4-phenoxy-quinazolin-6yl)benzaldehyde15 (3.78 g, 11.6 mmol) followed by the dropwise addition of acetic aciduntil the pH was approximately 6. NaCNBH₃ was added to the reactionmixture which was then allowed to stir overnight at room temperatureunder an atmosphere of N₂. The solution was diluted with CHCl₃ andwashed 3× with aqueous NaHCO₃ until the pH was approximately 9. Theorganic layer was separated, dried (MgSO₄) and removed under reducedpressure to provide a yellow viscous oil. The residue was purified byflash chromatography (silica gel, EtOAc-5% MeOH/EtOAc) to provide (3.51g, 8.28 mmol) compound 16 as a white solid in 71% yield. For compound16: ¹H NMR (CDCl₃ ) δ 8.75 (s, 1H), 8.54 (d, 1H J=2 Hz), 8.17 (dd, 1HJ=8.4 and 2.4 Hz), 8.05 (d, 1H, J=8.4 Hz), 7.66 (d, 2H, J=8 Hz), 7.48(m, 2H), 7.39 (m, 2H), 7.32 (m, 1H), 7.25 (m, 2H), 3.65 (s, 2H), 3.44(d, 2H, J=3.6 Hz), 3.02 (d, 2H, J=8.8 Hz), 2.38 (d, 2H, J=8.4 Hz), 1.62(m, 1H), 1.30 (s, 2H); MS (Cl) m/e 423 (M⁺+1, 100).

[0129] (3-{4-[4-(1-Cyclopropylmethyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)methanol(18):

[0130] To a 3 mL Wheaton vial was added{3-[4-(4-phenoxy-quinazolin-6-yl)-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol16 (100 mg, 0.24 mmol), 1-cyclopropylmethyl-1H-indol-5-ylamine 19 (48mg, 0.26 mmol), pyridinium hydrochloride (33 mg, 0.284 mmol), and phenol(155 mg, 1.652 mmol). The vial was capped and heated overnight at 110°C. The vial was cooled to room temperature and the residue taken up inCHCl₃ and washed with 15% aqueous NaOH, water, brine, and dried (MgSO₄).The solvent was removed and the residue purified by flash chromatography(silica gel, EtOAc:MeOH, 95:5) to provide compound 18 (88 mg, 0.159mmol) as a light brown solid in 67% yield. For compound 18: MS (Cl) m/e515 (M⁺+1, 100); HPLC, rt=4.83 min.

[0131] Method B: Synthesis of8-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol

[0132] (1 -Benzenesulfonyl-1H-indol-5-yl)-(6-iodo-quinazolin4-yl)-amine(20): 6-iodo-4-chloroquinazoline 13 (2.38 g, 8.20 mmol) and5-amino-1-benzenesulfonylindole 21 (2.46 g, 9.00 mmol) were combined inDCE (20 mL) and t-butanol (20 mL). The resulting mixture was heated atreflux under nitrogen for 18 hours to form a bright yellow suspension.Upon cooling the solids were filtered and rinsed with CH₂Cl₂ and placedunder high vacuum to remove any excess solvent. The title compound (3.23g, 75%) was obtained as a yellow solid. For compound 20: ¹H NMR(DMSO-d₆; 400 MHz): δ: 10.05 (s, 2H,), 8.93 (s, 1H), 8.53 (s, 1H), 8.25(m, 1H,), 8.10 (m, 5H), 7.97 (m, 3H), 7.82 (m, 2H), 7.70 (m, 2H), 7.65(m, 2H), 6.88 (d, 1H, J=3.57 Hz).

[0133]4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzaldehyde(22):

[0134] To a solution of toluene (100 mL) in a 500 mL round-bottom flaskequipped with a reflux condenser was added1,4-bis(diphenyl)phosphino)-butane (4.25 mg, 0.997 mmol) andbis(benzonitrile)dichloro-palladium (385 g, 0.997 mmol). Nitrogen wasbubbled through the reaction mixture for 1 minute and the resultingsuspension was stirred at room temperature for 30 minutes. THF (125 mL)and EtOH (50 mL) were then added. To the resulting mixture was added(1-benzenesulfonyl-1H-indol-5-yl)-(6-iodo-quinazolin-4-yl)-amine 20 (3.5g, 6.6 mmol), 4-formylphenylboronic acid (1.99 g, 13.3 mmol) and 2M aqNa₂CO₃ (6.7 mL). The mixture was heated at reflux under an atmosphere ofN₂ for 15 hours. The solvent was removed under reduced pressure and theresidue was purified using flash chromatography (silica gel,EtOAc/hexanes 1:1) to provide 3.1 g of4-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzaldehyde22 in 92% yield. ¹H NMR (DMSO-d₆; 400 MHz): δ:9.24 (s, 1H, NH), 8.84 (s,1H), 8.33 (dd, 1H, J=8.9 Hz and1.7 Hz), 8.01 (m, 4H), 7.90 (m, 2H), 7.70(m, 2H), 7.60 (m, 3H), 6.92 (dd, 1H, J=3.7 Hz and 0.6 Hz); MS (Cl) m/e505.1 (M⁺+1, 100).

[0135] 8-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol(23):

[0136] To a solution of CHCl₃ (1.5 mL) and MeOH (3 mL) in a round-bottomflask under N₂ was added 8-aza-bicyclo[3.2.1]octan-3-ol 24 (70 mg, 0.495mmol). AcOH was added to adjust the pH to 5. To the amine solution wasadded4-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzaldehyde22 (100 mg, 0.198 mmol) and the resulting solution was stirred at roomtemperature for 3 hours. NaCNBH₃ was added to the reaction mixture whichwas then allowed to stir overnight at room temperature under anatmosphere of N₂. The solution was diluted with CH₂Cl₂ and poured into1N NaOH (10 mL). The aqueous layer was separated and extracted withanother 2×15 mL of CH₂Cl₂. The organic layers were dried (MgSO₄) and thesolvent was removed under reduced pressure to provide a yellow viscousoil. The residue was purified by flash chromatography (silica gel,CH₂Cl₂-10% MeOH/CH₂Cl₂) to provide 45 mg of compound 23 as a white solidin 36% yield. HPLC, rt=5.25 min; MS (Cl) m/e 616.2 (M⁺+1, 100).

[0137] The following examples were prepared following either method A ormethod B as described above. In the Table, the term “min” refers tominutes. TABLE Example Method of LRMS Number preparation IUPAC name(MH+) HPLC 1 A {6-[4-(6-Amino-3-aza-bicyclo[3.1.0]hex-3- 587.2 7.99 minylmethyl)-phenyl]-quinazolin-4-yl}-(1-benzenesulfonyl-1H-indol-5-yl)-amine 2 A{6-[4-(6-Amino-3-aza-bicyclo[3.1.0]hex-3- 498.3 5.09 minylmethyl)-phenyl]-quinazolin-4-yl}-(4- benzyl-phenyl)-amine 3 A{6-[4-(6-Amino-3-aza-bicyclo[3.1.0]hex-3- 500.3 4.93 minylmethyl)-phenyl]-quinazolin-4-yl}-(4- phenoxy-phenyl)-amine 4 A(3-{4-[4-(4-Benzyl-phenylamino)- 513.2 5.44 minquinazolin-6-yl]-benzyl}-3-aza- bicyclo[3.1.0]hex-6-yl)-methanol 5 A(3-{4-[4-(4-Phenoxy-phenylamino)- 515.4 5.27 minquinazolin-6-yl]-benzyl}-3-aza- bicyclo[3.1.0]hex-6-yl)-methanol 6 A(3-{4-[4-(1-Benzenesulfonyl-1H-indol-5- 602.3 5.17 minylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 7 B (6-{4-[(1-Aza-bicyclo[2.2.2]oct-3-526.4 5.43 min ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(4-phenoxy-phenyl)-amine 8 B (6-{4-[(1-Aza-bicyclo[2.2.2]oct-3-526.4 5.52 min ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(4-benzyl-phenyl)-amine 9 B (6-{4-[(1-Aza-bicyclo[2.2.2]oct-3- 613.4(−) 5.33 min ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(1-benzenesulfonyl-1H-indol-5-yl)- amine 10 B(6-{4-[(3-Aza-bicyclo[3.1.0]hex-6- 500.3 4.93 minylamino)-methyl]-phenyl}-quinazolin-4- yl)-(4-phenoxy-phenyl)-amine 11 B(6-{4-[(3-Aza-bicyclo[3.1.0]hex-6- 498.3 5.10 minylamino)-methyl]-phenyl}-quinazolin-4- yl)-(4-benzyl-phenyl)-amine 12 B3-{4-[4-(4-Benzyl-phenylamino)- 558.3 4.47 min/5.77 minquinazolin-6-yl]-benzylamino}-8-methyl- diastereomer8-aza-bicyclo[3.2.1]octan-6-ol 13 B (6-{4-[(3-Aza-bicyclo[3.1.0]hex-6-587.2 4.80 min ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(1-benzenesulfonyl-1H-indol-5-yl)- amine 14 A(4-Benzyl-phenyl)-{6-[4-(6- 527.3 6.06 minmethoxymethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}- amine 15 A{6-[4-(6-Methoxymethyl-3-aza- 529.4 5.86 minbicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-(4-phenoxy-phenyl)- amine 16 A(1-Benzenesulfonyl-1H-indol-5-yl)-{6-[4- 616.2 5.64 min(6-methoxymethyl-3-aza- bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-amine 17 B (3-{4-[4-(4-Phenoxy-phenylamino)- 543.3 5.93min quinazolin-6-yl]-benzylamino}- bicyclo[2.2.1]hept-2-yl)-methanol 18B (3-{4-[4-(4-Benzyl-phenylamino)- 541.3 6.15 minquinazolin-6-yl]-benzylamino}- bicyclo[2.2.1]hept-2-yl)-methanol 19 B(3-{4-[4-(1-Benzenesulfonyl-1H-indol-5- 630.2 5.78 minylamino)-quinazolin-6-yl]-benzylamino}-bicyclo[2.2.1]hept-2-yl)-methanol 20 A(4-Benzyl-phenyl)-(6-{4-[(8-methyl-8-aza- 540.4 5.97 minbicyclo[3.2.1]oct-3-ylamino)-methyl]- phenyl}-quinazolin-4-yl)-amine 21A (6-{4-[(8-Methyl-8-aza-bicyclo[3.2.1]oct- 542.3 5.76 min3-ylamino)-methyl]-phenyl}-quinazolin-4- yl)-(4-phenoxy-phenyl)-amine 22A (1-Benzenesulfonyl-1H-indol-5-yl)-(6-{4- 629.2 5.60 min[(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-methyl]-phenyl}-quinazolin-4- yl)-amine 23 A(3-{4-[4-(4-[1,2,3]Thiadiazol-5-yl- 507.3 4.41 minphenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 24 A(3-{4-[4-(4-Cyclohexyl-phenylamino)- 505.4 6.11 minquinazolin-6-yl]-benzyl}-3-aza- bicyclo[3.1.0]hex-6-yl)-methanol 25 B8-Methyl-3-{4-[4-(4-phenoxy- 558.3 5.64 minphenylamino)-quinazolin-6-yl]- benzylamino}-8-aza-bicyclo[3.2.1]octan-6-ol 26 B 3-{4-[4-(1-Benzyl-1H-indol-5-ylamino)- 595.3 5.44 minquinazolin-6-yl]-benzylamino}-8-methyl- 8-aza-bicyclo[3.2.1]octan-6-ol27 B 3-{4-[4-(1-Benzenesulfonyl-1H-indol-5- 645.3 5.53 minylamino)-quinazolin-6-yl]-benzylamino}-8-methyl-8-aza-bicyclo[3.2.1]octan-6-ol 28 A(3-{4-[4-(4-p-Tolyloxy-phenylamino)- 529.4 5.63 minquinazolin-6-yl]-benzyl}-3-aza- bicyclo[3.1.0]hex-6-yl)-methanol 29 A(3-{4-[4-(Biphenyl-4-ylamino)-quinazolin- 499.3 5.36 min6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6- yl)-methanol 30 A(3-{4-[4-(4-Ethyl-phenylamino)- 451.3 4.73 minquinazolin-6-yl]-benzyl}-3-aza- bicyclo[3.1.0]hex-6-yl)-methanol 31 A4-{6-[4-(6-Hydroxymethyl-3-aza- 542.2 4.30 minbicyclo[3.1.0]hex-3-ylmethyl)-phenyl]- quinazolin-4-ylamino}-N-phenyl-benzamide 32 A N,N-Diethyl-3-{6-[4-(6-hydroxymethyl-3- 522.3 4.05 minaza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-ylamino}-benzamide 33 A[3-(4-{4-[3-Methyl-4-(pyridin-2- 544.3 4.41 minylmethoxy)-phenylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]- methanol 34 A(3-{4-[4-(4-Benzyloxy-phenylamino)- 529.3 5.21 minquinazolin-6-yl]-benzyl}-3-aza- bicyclo[3.1.0]hex-6-yl)-methanol 35 A[3-(4-{4-[1-(Propane-2-sulfonyl)-1H-indol- 568.3 4.73 min5-ylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-methanol 36 B8-Methyl-3-(4-{4-[1-(propane-2-sulfonyl)- 611.2 5.10 min1H-indol-5-ylamino]-quinazolin-6-yl}-benzylamino)-8-aza-bicyclo[3.2.1]octan- 6-ol 37 A(3-{4-[4-(1-Benzenesulfonyl-2-methyl- 616.2 5.47 min1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)- methanol 38 A(3-{4-[4-(1-Benzyl-1H-indazol-5- 553.3 4.69 minylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 39 A(3-{4-[4-(1-Methanesulfonyl-1H-indol-5- 540.2 4.21 minylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 40 A(3-{4-[4-(1-Ethanesulfonyl-1H-indol-5- 554.2 4.47 minylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 41 B(1-Benzenesulfonyl-1H-indol-5-yl)-(6-{4- 588.2 5.61 min[(3-oxa-bicyclo[3.1.0]hex-6-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-amine 42 B8-{4-[4-(1-Benzenesulfonyl-1H-indol-5- 616.2 5.25 minylamino)-quinazolin-6-yl]-benzyl}-8-aza- bicyclo[3.2.1]octan-3-ol 43 B8-(4-{4-[1-(Propane-2-sulfonyl)-1H-indol- 582.2 4.84/4.96 min5-ylamino]-quinazolin-6-yl}-benzyl)-8- aza-bicyclo[3.2.1]octan-3-ol 44 B8-{4-[4-(4-Phenoxy-phenylamino)- 529.3 5.35 minquinazolin-6-yl]-benzyl}-8-aza- bicyclo[3.2.1]octan-3-ol 45 B8-{4-[4-(1-Benzyl-1H-indol-5-ylamino)- 566.3 5.23 minquinazolin-6-yl]-benzyl}-8-aza- (+) bicyclo[3.2.1]octan-3-ol 46 A(3-{5-[4-(4-Phenoxy-phenylamino)- 516.2 5.04 minquinazolin-6-yl]-pyridin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 47 A(3-{5-[4-(1-Benzenesulfonyl-1H-indol-5- 603.2 4.98 minylamino)-quinazolin-6-yl]-pyridin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)- methanol 48 A(3-{5-[4-(1-Benzyl-1H-indazol-5- 554.2 4.48 minylamino)-quinazolin-6-yl]-pyridin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)- methanol 49 A(3-{4-[4-(6-Phenoxy-pyridin-3-ylamino)- 516.2 4.74 minquinazolin-6-yl]-benzyl}-3-aza- bicyclo[3.1.0]hex-6-yl)-methanol 50 A(3-{5-[4-(4-Benzyloxy-phenylamino)- 530.2 4.98 minquinazolin-6-yl]-pyridin-2-ylmethyl-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 51 A[3-(5-{4-[3-Methyl-4-(pyridin-2- 545.2 4.15 minylmethoxy)-phenylamino]-quinazolin-6- yl}-pyridin-2-ylmethyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-methanol 52 A (3-{5-[4-(4-Benzyl-phenylamino)-514.3 5.18 min quinazolin-6-yl]-pyridin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 53 A {3-[4-(4-Phenoxy-phenylamino)-452.3 7.95 min quinazolin-6ylmethyl]-3-aza-bicyclo[3.1.0]hex-6-yl}methanol 54 B(5-{4-[4-(1-Benzenesulfonyl-1H-indol-5 630.1 5.43 minylamino)-quinazolin-6-yl]-benzyl}-5-aza spiro[2.5]oct-1-yl)-methanol 55B (5-{4-[4-(4-Phenoxy-phenylamino)- 543.2 5.59 minquinazolin-6-yl]-benzyl}-5-aza spiro[2.5]oct-1-yl)-methanol 56 B(6-{4-[4-(1-Benzenesulfonyl-1H-indol-5- 630.2 5.36 minylamino)-quinazolin-6-yl]-benzyl}-6-aza- spiro[2.5]oct-1-yl)-methanol 57B (6-{4-[4-(4-Phenoxy-phenylamino)- 543.2 5.53 minquinazolin-6-yl]-benzyl}-6- azaspiro[2.5]oct-1-yl)-methanol 58 B(5-{4-[4-(1-Benzenesulfonyl-1H-indol-5- 616.1 5.34 minylamino)-quinazolin-6-yl]-benzyl}-5-aza spiro[2.4]hept-1-yl)-methanol 59B (5-{4-[4-(4-Phenoxy-phenylamino)- 529.4 5.50 minquinazolin-6-yl]-benzyl}-5-aza (+) spiro[2.4]hept-1-yl)-methanol 60 B(5-{4-[4-(4-Phenoxy-phenylamino)- 543.2 5.91 minquinazolin-6-yl]-benzyl}-5-aza- spiro[2.5]oct-1-yl)-methanol

[0138] The following compounds (and their pharmaceutically acceptablesalts and solvates, and all stereoisomers including any endo and exoisomers) which are part of the present invention, may be prepared usingthe methods described above and/or methods familiar to those skilled inthe art:

[0139](3-{4-[4-(3-Fluoro-4-phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0140](3-{4-[4-(4-Phenoxy-3-trifluoromethyl-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0141](3-{4-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0142](5-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-5-aza-spiro[2.5]oct-1-yl)-methanol;

[0143]8-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol;

[0144]8-{4-[4-(1-Benzyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-8-aza-bicyclo-[3.2.1]octan-3-ol;

[0145]8-{4-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol;

[0146]8-{4-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol;

[0147]8-(4-{4-[1-(Propane-2-sulfonyl)-1H-indol-5-ylamino]-quinazolin-6-yl}-benzyl)-8-aza-bicyclo[3.2.1]octan-3-ol;

[0148](3-{4-[4-(4-Benzyloxy-3-methyl-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0149][3-(4-{4-[1-(4-Methyl-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl]-benzyl)-3-aza-bicyclo[3.2.1]hex-6-yl]-methanol;

[0150][3-(4-{4-[1-(4-Methoxy-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-methanol;

[0151][3-(4-{4-[1-(3-Methyl-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-methanol;

[0152][3-(4-{4-[1-(3-Methoxy-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-methanol;

[0153][3-(4-{4-[1-(2-Flouro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-methanol;

[0154](3-{4-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0155]{6-[4-(6-Dimethylamino-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-(3-methoxy-4-phenoxy-phenyl)-amine;

[0156]{6-[4-(6-Dimethylamino-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-(3-methyl-4-phenoxy-phenyl)-amine;

[0157](3-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0158](3-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0159]{6-[3-(6-Dimethylamino-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]quinazolin-4-yl}-(3-methoxy-4-phenoxy-phenyl)-amine;

[0160]{6-[3-(6-Dimethylamino-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]quinazolin-4-yl}-(3-methyl-4-phenoxy-phenyl)-amine;

[0161]{6-[3-(6-Amino-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-(3-methoxy-4-phenoxy-phenyl)-amine;

[0162](3-{4-[4-(3-Methyl-4-o-tolyloxy-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

[0163][3-(4-{4-[4-(2-Methoxy-phenoxy)-3-methyl-phenylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-methanol;and,

[0164][3-(4-{4-[4-(2-Fluoro-phenoxy)-3-methyl-phenylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-methanol.

1. A compound of the formula 1

or a pharmaceutically acceptable salt or solvate thereof, wherein: X isN or CH; A represents a fused 5, 6 or 7-membered ring optionallycontaining 1 to 4 heteroatoms which may be the same or different andwhich are selected from —N(R¹)—, O, and S(O)_(j), wherein j is aninteger from 0 to 2, the fused ring containing a total of 1, 2 or 3double bonds inclusive of the bond in the pyridine or pyrimidine ring towhich it is fused wherein the R¹ group attached to the nitrogen isabsent if a double bond includes the foregoing optional nitrogen moiety—N(R¹)—, with the proviso that the fused ring does not form part of apurine and that the fused ring does not contain two adjacent O orS(O)_(j) atoms, and wherein the carbon atoms of the A moiety areoptionally substituted by 1 to 3 R⁵ groups; each R¹ and R² isindependently H or C₁-C₆ alkyl; R³ is —(CR¹R²)_(m)—R⁸ wherein m is 0 or1; or R¹ and R³ are taken together to form a group of the formula

wherein said group is optionally substituted with 1 to 3 R⁵ groups; R⁴is —(CR¹R²)_(t)(C₆-C₁₀ aryl) or —(CR¹R²)_(t)(4-10 memberedheterocyclic), wherein t is an integer from 0 to 5, wherein said R⁴groups are substituted with 1 to 3 groups independently selected from—(CR¹R²)_(q)NR¹R⁹, —(CR¹R²)_(q)NR⁹(C₁-C₆ alkanoyl),—(CR¹R²)_(q)O(CR¹R²)_(r)R⁹, and —(CR¹R²)_(q)R⁹ wherein q and r are eachindependently an integer from 0 to 5, and wherein the heterocyclic, aryland alkyl moieties of the foregoing groups are optionally substitutedwith 1 to 3 R¹⁰ groups; each R⁵ is independently selected from halo,hydroxy, —NR¹R², C₁-C₆ alkyl, trifluoromethyl, C₁-C₆ alkoxy, andtrifluoromethoxy; each R⁶ and R⁷ is independently selected from H, C₁-C₆alkyl, —(CR¹R²)_(t)(C₆-C₁₀aryl), and —(CR¹R²)_(t)(4-10 memberedheterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbonatoms of the heterocyclic group are optionally substituted with an oxo(═O) moiety, and the alkyl, aryl and heterocyclic moieties of theforegoing R⁶ and R⁷ groups are optionally substituted with 1 to 3substituents independently selected from halo, cyano, nitro, —NR¹R²,trifluoromethyl, trifluoromethoxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, hydroxy, and C₁-C₆ alkoxy; each R⁸ is independently selectedfrom —(CR¹R²)_(t)(C₆-C₁₀ aryl) and —(CR¹R²)_(t)(4-10 memberedheterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbonatoms of the heterocyclic group are optionally substituted with an oxo(═O) moiety, and each of the foregoing R⁸ groups is optionallysubstituted with 1 to 5 R¹⁰ groups; R⁹ is a fused or bridged bicyclicring or a spirocyclic ring, wherein said ring contains from 5 to 12carbon atoms in which up to 2 carbon atoms are optionally replaced witha hetero moiety selected from O, S(O)_(j) wherein j is an integer from 0to 2, and —NR¹¹—, provided that two O atoms, two S(O)_(j) moieties, an Oatom and a S(O)_(j) moiety, an N atom and an S atom, or an N atom and anO atom are not attached directly to each other, and wherein said ring issaturated or partially unsaturated with up to two carbon-carbon doublebonds, and the carbon atoms of said ring are optionally substituted with1 to 4 R¹⁰ groups; or where R⁹ is as —NR¹R⁹ then R⁹ optionally can betaken together with R¹ and the nitrogen to which R¹ and R⁹ are attachedto form a fused or bridged bicyclic ring or a spirocyclic ring, whereinsaid ring is saturated and contains from 5 to 12 carbon atoms in whichup to 2 carbon atoms are optionally replaced with a hetero moietyselected from O, S(O)_(j) wherein j is an integer from 0 to 2, and—NR¹—, provided that two O atoms, two S(O)_(j) moieties, or an O atomand a S(O)_(j) moiety are not attached directly to each other, andwherein the carbon atoms of said rings are optionally substituted with 1to 4 R¹⁰ groups; each R¹⁰ is independently selected from halo, cyano,nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, C₁-C₆ alkoxy,C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C(O)R⁵, —C(O)OR⁶, —OC(O)R⁶,—NR⁶C(O)R⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷, —SO₂NR⁶R⁷, —S(O)_(j)(C₁-C₆alkyl) wherein j is an integer from 0 to 2,—(CR¹R²)_(q)C(O)(CR¹R²)_(t)(C₆-C₁₀ aryl),—(CR¹R²)_(q)C(O)(CR¹R²)_(t)(4-10 membered heterocyclic),—(CR¹R²)_(t)O(CR¹R²)_(q)(C₆-C₁₀ aryl), —(CR¹R²)_(t)O(CR¹R²)_(q)(4-10membered heterocyclic), —(CR¹R²)_(t)O(CR¹R²)_(q)(C₆-C₁₀ aryl),—(CR¹R²)_(t)O(CR¹R²)_(q)(4-10 membered heterocyclic),—(CR¹R²)_(q)SO₂(CR¹R²)_(t)(C₆-C₁₀ aryl, and—(CR¹R²)_(q)SO₂(CR¹R²)_(t)(4-10 membered heterocyclic), wherein q and tare each independently an integer from 0 to 5, 1 or 2 ring carbon atomsof the heterocyclic moieties of the foregoing R¹⁰ groups are optionallysubstituted with an oxo (═O) moiety, and the alkyl, alkenyl, alkynyl,aryl and heterocyclic moieties of the foregoing R¹⁰ groups areoptionally substituted with 1 to 3 substituents independently selectedfrom halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR⁶,—C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —(CR¹R²)_(t)(C₆-C₁₀ aryl),and —(CR¹R²),(4-10 membered heterocyclic), wherein t is an integer from0 to 5; R¹¹ is H, C₁-C₆ alkyl, —C(O)R⁶ or —SO₂R⁶; and wherein any of theabove-mentioned substituents comprising a CH₃ (methyl), CH₂ (methylene),or CH (methine) group which is not attached to a halogeno, SO or SO₂group or to a N, O or S atom optionally bears on said group asubstituent selected from hydroxy, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and—NR¹R².
 2. A compound according to claim 1 wherein the A moiety of thecompound of formula 1 is selected from

wherein the above A moieties bear an R⁴ group as a substituent andoptionally bear 1 to 3 R⁵ groups as substituents.
 3. A compoundaccording to claim 1 wherein the A moiety of the compound of formula 1is selected from

wherein the above A moieties bear an R⁴ group as a substituent andoptionally bear 1 to 3 R⁵ groups as substituents.
 4. A compoundaccording to claim 1 wherein the A moiety of the compound of formula 1is selected from

wherein the above A moieties bear an R⁴ group as a substituent andoptionally bear 1 to 3 R⁵ groups as substituents.
 5. A compoundaccording to claim 1 wherein the A moiety of the compound of formula 1is selected from

wherein the above A moieties bear an R⁴ group as a substituent andoptionally bear 1 to 3 R⁵ groups as substituents.
 6. A compoundaccording to claim 1 wherein the A moiety of the compound of formula 1is

wherein the above A moieties bear an R⁴ group as a substituent andoptionally bear 1 to 3 R⁵ groups as substituents.
 7. A compoundaccording to claim 5 wherein R⁴is —(CR¹R²)_(t)(C₆-C₁₀ aryl) or—(CR¹R²)_(t)(4-10 membered heterocyclic), wherein t is an integer from 0to 5, wherein said R⁴ groups are substituted with 1 to 3 groupsindependently selected from —(CR¹R²)_(q)NR¹R⁹, —(CR¹R²)_(q)NR⁹(C₁-C₆alkanoyl), —(CR¹R²)_(q)O(CR¹R²)_(r)R⁹, and —(CR¹R²)_(q)R⁹ wherein q andr are each independently an integer from 0 to 3, and wherein theheterocyclic, aryl and alkyl moieties of the foregoing groups areoptionally substituted with 1 to 3 R¹⁰ groups.
 8. A compound accordingto claim 6 wherein R⁴is —(CR¹R²)_(t)(C₆-C₁ aryl) or —(CR¹R²)_(t)(4-10membered heterocyclic), wherein t is an integer from 0 to 5, whereinsaid R⁴ groups are substituted with 1 to 3 groups independently selectedfrom —(CR¹R²)_(q)NR¹R⁹, —(CR¹R²)_(q)NR⁹(C₁-C₆ alkanoyl),—(CR¹R²)_(q)O(CR¹R²)_(r)R⁹, and —(CR¹R²)_(q)R⁹ wherein q and r are eachindependently an integer from 0 to 3, and wherein the heterocyclic, aryland alkyl moieties of the foregoing groups are optionally substitutedwith 1 to 3 R¹⁰ groups.
 9. A compound according to claim 5 wherein R³ is—(CR¹R²)_(m)—R⁸ wherein m is 0 or 1 and R⁸ is selected from—(CR¹R²)_(t)(phenyl), —(CR¹R²)_(t)(pyridyl), —(CR¹R²)_(t)(pyrimidinyl),—(CR¹R²)_(t)(indolyl), —(CR¹R²)_(t)(indazolyl) and—(CR¹R²)_(t)(benzimidazolyl), wherein t is an integer from 0 to 5, andeach of the foregoing R⁸ groups is optionally substituted with 1 to 5R¹⁰ groups.
 10. A compound according to claim 6 wherein R³ is—(CR¹R²)_(m)—R⁸ wherein m is 0 or 1 and R⁸ is selected from—(CR¹R²)_(t)(phenyl), —(CR¹R²)_(t)(pyridyl), —(CR¹R²)_(t)(pyrimidinyl),—(CR¹R²)_(t)(indolyl), —(CR¹R²)_(t)(indazolyl) and—(CR¹R²)_(t)(benzimidazolyl), wherein t is an integer from 0 to 5, andeach of the foregoing R⁸ groups is optionally substituted with 1 to 5R¹⁰ groups.
 11. A compound according to claim 7 wherein R³ is—(CR¹R²)_(m)—R⁸ wherein m is 0 or 1 and R⁸ is selected from—(CR¹R²)_(t)(phenyl), —(CR¹R²)_(t)(pyridyl), —(CR¹R²)_(t)(pyrimidinyl),—(CR¹R²)_(t)(indolyl), —(CR¹R²)_(t)(benzimidazolyl), wherein t is aninteger from 0 to 5, and each of the foregoing R⁸ groups is optionallysubstituted with 1 to 5 R¹⁰ groups.
 12. A compound according to claim 8wherein R³ is —(CR¹R²)_(m)—R⁸ wherein m is 0 or 1 and R⁸ is selectedfrom —(CR¹R²)_(t)(phenyl), —(CR¹R²)_(t)(pyridyl),—(CR¹R²)_(t)(pyrimidinyl), —(CR¹R²)_(t)(indolyl),—(CR¹R²)_(t)(indazolyl) and —(CR¹R²)_(t)(benzimidazolyl), wherein t isan integer from 0 to 5, and each of the foregoing R⁸ groups isoptionally substituted with 1 to 5 R¹⁰ groups.
 13. A compound accordingto claim 1 selected from the group consisting of:{6-[4-(6-Amino-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-(4-phenoxy-phenyl)-amine;(3-{4-[4-(4-Benzyl-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;(3-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;(3-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;(6-{4-[(1-Aza-bicyclo[2.2.2]oct-3-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(4-phenoxy-phenyl)-amine;(6-{4-[(1-Aza-bicyclo[2.2.2]oct-3-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(4-benzyl-phenyl)-amine;6-{4-[(1-Aza-bicyclo[2.2.2]oct-3-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(1-benzenesulfonyl-1H-indol-5-yl)-amine;6-{4-[(3-Aza-bicyclo[3.1.0]hex-6-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(4-phenoxy-phenyl)-amine;3-{4-[4-(4-Benzyl-phenylamino)-quinazolin-6-yl]-benzylamino}-8-methyl-8-aza-bicyclo[3.2.1]octan-6-ol;(4-Benzyl-phenyl)-{6-[4-(6-methoxymethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-amine{6-[4-(6-Methoxymethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-}-(4-phenoxy-phenyl)-amine;(3-{4-[4-(4-[1,2,3]Thiadiazol-5-yl-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;(3-{4-[4-(4-Cyclohexyl-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;(3-{4-[4-(4-p-Tolyloxy-phenylamino)-quinazolin)-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;(3-{4-[4-(Biphenyl-4-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;(3-{4-[4-(4-Ethyl-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;4-{6-[4-(6-Hydroxymethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-ylamino)-N-phenyl-benzamide;[3-(4-{4-[1-(Propane-2-sulfonyl)-1H-indol-5-ylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-methanol;(3-{4-[4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;(1-Benzenesulfonyl-1H-indol-5-yl)-(6-{4-[(3-oxa-bicyclo[3.1.0]hex-6-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-amine;8-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}aza-bicyclo[3.2.1]octan-3-ol;8-(4-{4-[1-(Propane-2-sulfonyl)-1H-indol-5-ylamino]-quinazolin-6-yl}-benzyl)-8-aza-bicyclo[3.2.1]octan-3-ol;8-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol;8-{4-[4-(1-Benzyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol;(3-{4-[4-(6-Phenoxy-pyridin-3-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;(3-{5-[4-(4-Benzyl-phenylamino)-quinazolin-6-yl]-pyridin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;{3-[4-(4-Phenoxy-phenylamino)-quinazolin-6ylmethyl]-3-aza-bicyclo[3.1.0]hex-6-yl}methanol;(5-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-5-aza-spiro[2.5]oct-1-yl)-methanol;(5-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-5-aza-spiro[2.5]oct-1-yl)-methanol;(6-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-6-aza-spiro[2.5]oct-1-yl)-methanol;(6-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-6-azaspiro[2.5]oct-1-yl)-methanol;(5-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-5-aza-spiro[2.4]hept-1-yl)-methanol;(5-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-5-aza-spiro[2.4]hept-1-yl)-methanol;(5-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-5-aza-spiro[2.5]oct-1-yl)-methanol;and the pharmaceutically acceptable salts and solvates of the foregoingcompounds.
 14. A method for the treatment of abnormal cell growth in amammal comprising administering to said mammal an amount of a compoundof claim 1 that is effective in treating abnormal cell growth.
 15. Amethod according to claim 14 wherein said abnormal cell growth iscancer.
 16. A method according to claim 15 wherein said cancer isselected from lung cancer, bone cancer, pancreatic cancer, skin cancer,cancer of the head or neck, cutaneous or intraocular melanoma, uterinecancer, ovarian cancer, rectal cancer, cancer of the anal region,stomach cancer, colon cancer, breast cancer, uterine cancer, carcinomaof the fallopian tubes, carcinoma of the endometrium, carcinoma of thecervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin'sDisease, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, prostate cancer, chronic oracute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer ofthe kidney or ureter, renal cell carcinoma, carcinoma of the renalpelvis, neoplasms of the central nervous system (CNS), primary CNSlymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers.
 17. A methodaccording to claim 14 wherein said abnormal cell growth is a benignproliferative disease.
 18. A method according to claim 17 wherein saidabnormal cell growth is selected from psoriasis, benign prostatichypertrophy and restinosis.
 19. A method for the treatment of abnormalcell growth in a mammal which comprises administering to said mammal anamount of a compound of claim 1 that is effective in treating abnormalcell growth in combination with an anti-tumor agent selected from thegroup consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, antibodies, cytotoxics, anti-hormones, andanti-androgens.
 20. A pharmaceutical composition for the treatment ofabnormal cell growth in a mammal comprising an amount of a compound ofclaim 1 that is effective in treating abnormal cell growth, and apharmaceutically acceptable carrier.
 21. A method of preparing acompound of claim 1 which comprises either (a) reacting a compound ofthe formula 5 with a compound of the formula 6

wherein Z is a leaving group and A, X, R¹, R³, and R⁴ are as defined inclaim 1, or (b) reacting a compound of the formula 2 with a compound ofthe formula 6

wherein X, A, R¹, and R³ are as defined in claim 1 and Z¹ is anactivating group, to provide an intermediate of the formula 7

wherein Z¹, X, A, R¹, and R³ are as defined in claim 1, and treating thecompound of formula 7 with a coupling partner of the formulaX¹—(CR¹R²)_(t)(C₆-C₁₀ aryl) or X¹—(CR¹R²)_(t)(4-10 memberedheterocyclic), wherein t, R¹ and R² are as defined in claim 1 asprovided in the definition of R⁴, the aryl and heterocyclic groups ofthe foregoing groups are substituted with a group that includes analdehyde or acid moiety, and X¹ is —B(OH)₂ or —Sn(C₁-C₅ alkyl)₃, toprovide a compound of formula 8

wherein X, A, R¹, and R³ are as defined above, and Z² is—(CR¹R²)_(t)(C₆-C₁₀ aryl) or —(CR¹R²)_(t)(4-10 membered heterocyclic),wherein t, R¹ and R² are as defined in claim 1, and the aryl andheterocyclic groups of the foregoing Z² groups are substituted with agroup that includes an aldehyde or acid moiety, and modifying saidaldehyde or acid moiety to introduce a group selected from—(CR¹R²)_(q)NR¹R⁹, —(CR¹R²)_(q)NR⁹(C₁-C₆ alkanoyl), —(CR¹R²)_(q)OR⁹, and—(CR¹R²)_(q)R⁹, wherein R¹, R², R⁹, and q are as defined in thedefinition of R⁴ in claim 1.